The T cell derived interleukin-4 (IL-4) was originally described as a murine factor that could co-stimulate the proliferation of activated B cells [Howard et al., J. Exp. Med. 155:914 (1982)]. Subsequently, it was demonstrated that murine IL-4 could exert a variety of biological effects on B cells [Paul et al., Ann. Rev. Immunol. 5:429 (1987); Noelle et.al., Proc. Natl. Acad. Sci. U.S.A. 81:6149 (1984); Roehm et al., J. Exp. Med. 160:679 (1984); Vitetta et al., J. Exp. Med. 162:1726 (1985); Coffman et al., J. Immunol. 136:4538 (1986); Coffman et al., J. Immunol. 136:949 (1986)] and other cell types including T cells [Mosmann et al., Proc. Natl. Acad. Sci. U.S.A. 83:5654 (1986); Fernandez-Botran et al., J. Exp. Med. 164:580 (1986); Hu-Li et al., J. Exp. Med. 165:157 (1987); Grabstein et al., J. Immunol. 139:1148 (1987); Zlotnick et al., Proc. Natl. Acad. Sci. U.S.A. 84:3856 (1987)], hematopoietic progenitor cells [Rennick et al., Proc. Natl. Acad. Sci. U.S.A. 84:6889 (1987); Peschel et al., Blood 70:254 (1987)] and mast cells (Mosmann, supra).
Based on homology with mudne IL-4, a cDNA encoding human interleukin-4 (hulL-4) has been cloned [Yokota et al., Proc. Natl. Acad. Sci. U.S.A. 83:5894 (1986)] and expressed in both mammalian [Le et al., J. Biol. Chem. 263:10817 (1988); Sonoda et al., J. Biotechnology 9:61 (1988); Takebe et al., Mol. Cell Biol. 8:466 (1988)] and bacterial [van Kimmenade et al., Eur. J. Biochem. 173:109 (1988)] hosts. Like murine IL-4, recombinant hulL-4 (rhulL-4) is a pleiotropic lymphokine that acts on a variety of cell types. Thus, for example, rhulL-4 can induce the proliferation of both activated T and B lymphocytes [Spits et al., J. Immunol. 139:1142 (1987); DeFrance et al., J. Immunol. 139:1135 (1987)], enhance the expression of class II major histocompatibility antigens and the low affinity receptor for IgE on B cells [Rousset et al., J. Immunol. 140:2625 (1988); DeFrance et al., J. Exp. Med. 165:1459 (1987)] and induce production of IgE and other immunoglobulins [Pene et al., Proc. Natl. Acad. Sci. U.S.A. 85:6880 (1988)]. The ability of rhulL-4 to inhibit IL-2 dependent proliferation of chronic lymphocytic leukemic cells of B cell origin has suggested a clinical application in B cell neoplasms [Karray et al., J. Exp. Med. 168:85 (1988)].
The availability of milligram quantities of purified rhulL-4 has facilitated the initiation of studies of the structure and the structure-function relationships of the protein. The present invention relates to the discovery of conditions for producing crystalline rhulL-4. The invention further relates to the crystalline rhulL-4 itself. The crystals are suitable for X-ray diffraction studies and have applications in the purification and formulation of rhulL-4.